This invention relates to a novel class of compounds which exhibit analgesic activity.
Recently, endogenous substances having morphine-like properties have been extracted from mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature, 258, 577 (1975) as pentapeptides having the following sequences:
H-Tyr-Gly-Gly-Phe-Met-OH PA1 H-Tyr-Gly-Gly-Phe-Leu-OH. PA1 (a) substitution of Gly in position 2 by certain D- or .alpha.-aza-amino acids; PA1 (b) conversion of the terminal carboxyl to the methyl ester or the amide; PA1 (c) modification of the Phe in the 4-position by .alpha.-aza substitution, N-methylation, or hydrogenation of the aromatic ring. PA1 R.sub.1 is hydrogen or C.sub.1 -C.sub.3 primary alkyl; PA1 R.sub.2 is C.sub.1 -C.sub.4 primary or secondary alkyl, allyl, cyclopropylmethyl, C.sub.1 -C.sub.2 hydroxyalkyl, or --(CH.sub.2).sub.m --U--CH.sub.3 in which U is --S-- or &gt;S--O and m is 1 or 2; PA1 R.sub.3 is hydrogen, C.sub.1 -C.sub.4 primary or secondary alkyl, cyclopropylmethyl, allyl or propargyl; and PA1 Z is --CH.sub.2 OR.sub.4, ##STR4## in which R.sub.4 is hydrogen, acetyl, or acetoxymethyl and R.sub.5 is C.sub.1 -C.sub.3 alkyl.
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although methionine and leucine enkephalin have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
Therefore, since the discovery of the enkephalins, much effort has been devoted to preparing analogs of the enkephalins in the hope of finding compounds having enhanced activity and practical utility due to their bioavailability by parenteral or oral administration.
Dutta et al., Life Sciences 21, pp. 559-562 (1977) report certain structure modifications which, they suggest, tend to enhance potency. They suggest activity can be enhanced by any or all of the following:
In addition, Roemer et al., Nature 268, pp. 547-549 (1977), suggest modification of the Met.sup.5 to its corresponding carbinol and oxidation of the Met sulfur to the sulfoxide as useful modifications.
Another structural modifications of significance is that reported in Belgian Patent No. 859,026. This publication suggests enhancement of activity and bioavailability of enkephalin analogs by insertion of a D-amino acid residue in position 2, conversion of the terminal carboxyl to an amide, and N-alkylation of the amino acid residue in position 5.
A class of analogs of enkephalin having a high level of analgesic activity has now been discovered. These analogs are halogenated tetrapeptides which are structurally highly specific in terms both of the identity and the position of the halogen. The compounds of this invention are tetrapeptides having the residue of a p-fluoro-substituted L-phenylalanine in the 4-position of the peptide.
The literature recognizes other halogenated 4-phenylalanyl enkephalin analogs; however, they are not tetrapeptides, and they are not mono p-fluoro-substituted 4-phenylalanyl enkephalin analogs. A. R. Day et al., Res. Comm. in Chem. Path. and Pharmacol. 14 (4), 597-603 (1976) reports H-Tyr-Gly-Gly-pClPhe-Nle-OH. R. J. Miller et al., Vitamins and Hormones 36, 297-382, Academic Press (1978) mentions H-Tyr-D-Ala-Gly-pClPhe-D-Leu-OH; H-Tyr-D-Ala-Gly-p-ClPhe-D-Leu-OMe; and H-Tyr-D-Ala-Gly-p-ClPhe-D-Leu-NHEt. Pless et al., "Opioid Activity of Enkephalin Analogues," presented at the 15th European Peptide Symposium, Sept. 4-9, 1978, Gdansk, Poland, reports H-Tyr-D-Ala-Gly-pClPhe-Met(O)-OL. D. H. Coy et al., BBRC 83 (3), 977-983 (1978) mentions H-Tyr-D-Ala-Gly-F.sub.5 Phe-Met-NH.sub.2.
None of the above reports the compounds of this invention, and it has been discovered that both the identity and the position of the halogen play a significant role in the level of analgesic activity of the enkephalin analog.